Polymorphisms in the CTLA4 promoter sequence are associated with canine hypoadrenocorticism

Boag, Alisdair M.; Short, Andrea; Kennedy, Lorna J.; Syme, Hattie; Graham, Peter A.; Catchpole, Brian

Abstract

Background
Canine hypoadrenocorticism is an immune-mediated endocrinopathy that shares both clinical and pathophysiological similarities with Addison’s disease in humans. Several dog breeds are overrepresented in the disease population, suggesting that a genetic component is involved, although this is likely to be polygenic. Previous research has implicated CTLA4 as a potential susceptibility gene. CTLA4 is an important regulator of T cell function and polymorphisms/mutations in CTLA4 have been associated with a number of autoimmune phenotypes in both humans and rodent models of autoimmunity. The aim of the current study was to undertake a case:control association study of CTLA4 promotor polymorphisms in three dog breeds, cocker spaniels, springer spaniels and West Highland white terriers (WHWT).

Results
Polymorphisms in the CTLA4 promoter were determined by PCR and sequence-based typing. There were significant associations with three promoter haplotypes in cocker spaniels (p = 0.003). A series of SNPs were also associated with hypoadrenocorticism in cocker spaniels and springer spaniels, including polymorphisms in predicted NFAT and SP1 transcription factor binding sites.

Conclusions
This study provides further evidence that CTLA4 promotor polymorphisms are associated with this complex genetic disease and supports an immune mediated aetiopathogenesis of canine hypoadrenocorticism.

Citation

Boag, A. M., Short, A., Kennedy, L. J., Syme, H., Graham, P. A., & Catchpole, B. (2020). Polymorphisms in the CTLA4 promoter sequence are associated with canine hypoadrenocorticism. Canine Medicine and Genetics, 7, Article 2. https://doi.org/10.1186/s40575-020-0081-4

• Journal Article Type: Article
• Acceptance Date: Feb 18, 2020
• Online Publication Date: Mar 4, 2020
• Publication Date: Mar 4, 2020
• Deposit Date: Mar 13, 2020
• Publicly Available Date: Mar 13, 2020
• Journal: Canine Medicine and Genetics
• Electronic ISSN: 2662-9380
• Publisher: Springer Nature
• Peer Reviewed: Peer Reviewed
• Volume: 7
• Article Number: 2
• DOI: https://doi.org/10.1186/s40575-020-0081-4
• Keywords: Addison’s, Canine, CTLA-4, Hypoadrenocorticism, Promoter
• Public URL: https://nottingham-repository.worktribe.com/output/4136582
• Publisher URL: https://cgejournal.biomedcentral.com/articles/10.1186/s40575-020-0081-4
• Additional Information: Received: 7 November 2019; Accepted: 18 February 2020; First Online: 4 March 2020; : Ethical approval was granted by The Royal Veterinary College Institutional Ethics and Welfare Committee.; : Not applicable.; : Lorna J Kennedy is Managing Editor on Canine Medicine and Genetics. However, she will not be involved in the decision-making of this paper. The other authors declare no competing interests.